In our past studies we uncovered several lupus susceptibility genes that, either by themselves or by interacting with a variety of other genetic factors, modify both the induction and progression of autoimmune disease. We previously determined that mice deficient in the IgG receptor FcgammaRIIB develop spontaneous anti-nuclear antibodies and fatal glomerulonephritis. Characterization of other genetic modifiers of lupus in the FcgammaRIIB-deficient mouse model allowed us to determine that a mere duplication of the Tlr7 gene is sufficient to agravate autoimmune disease. We showed, using transgenic overexpression of TLR7, that TLR7 is essential to regulate autoimmunity and dendritic cell homeostasis. These mice provide a prime example of how important it is to control the expression of innate receptors. These studies provide a theoretical framework in which anti-viral innate responses, when not properly regulated, can result in autoreactivity and lethal inflammatory disease. We have analyzed the specific role of a variety of anti-viral pathways and their possible production of interferon in the development of autoimmune disease. In particular we have: 1) made considerable progress in understanding the cellular basis of the role of TLR7 in lupus including the identification of a novel population of atypical NK cells and the infiltration of CD8+ cells into brain in lupus-prone mice possibly contributing to brain pathology observed in SLE; 2) explored the role of additional endocytic TLRs, namely TLR9 and TLR3 in lupus and the interaction of these TLRs with TLR7 and 3) explored the possibility that various cytoplasmic sensors of viral RNA and DNA may also potentiate or modify the development of autoimmune disease. Studying the role of innate responses against pathogens in autoimmune-prone settings may shed light on gender bias, influence of infections, and the stochastic pathogenesis that is often seen in the development of autoimmunity In addition, we have collaborated with other members of the Malaria Research Program at NIAID to understand a possible link between resistance to malaria infection and autoimmunity. In collaboration with Dr. Sus group at LMVR, NIAID we are investigating innate pathways that are turned on in the context of murine malaria models. In collaboration with Dr. Crompton at LIG, NIAID, we are uncovering the presence of autoantibodies in samples recovered from malaria endemic areas. Overall these results point towards a possible role of autoreactive responses in developing long-term immunity to malaria.